tbuckley/cabot-search huggingface dataset:
Abstract 3507: β-Hydroxy-β-methylbutyrate (HMB) sensitizes murine pancreatic ductal adenocarcinoma (PDAC) to immunotherapy
Authors: Suhas K. Etigunta, Michael F. Coleman, Kristyn A. Liu, Alex J. Pfeil, Zhengrong Cui, Stephen D. Hursting
Journal: Cancer Research (2022)

Abstract Background: Pancreatic cancer is the fourth leading cause of cancer-related death in the United States. PDAC often presents at advanced tumor stages, resulting in poor survival rates. Immunotherapies such as inhibition of programmed death 1 (PD1) are effective in many cancers, but not in PDAC. HMB is a leucine metabolite that reduces PDAC progression and cachexia in association with enhanced antitumor immune responses. The purpose of this study was to determine if HMB treatment enhances immunotherapeutic response in PDAC. Methods: C57BL/6J mice bearing subcutaneously transplanted PANC02 tumors were fed either a control (AIN93G) or HMB (1% w/w) supplemented diet. Once tumors were palpable, mice were randomized for treatment with vehicle or anti-PD1 immunotherapy (n=12-13/group). Tumors were harvested and global transcriptomic analysis was performed. Results: Both HMB and anti-PD1 interventions alone were insufficient to reduce tumor growth. However, the combination of HMB and anti-PD1 resulted in significantly smaller tumors than the anti-PD1 alone group, indicating that HMB was able to stimulate PDAC response to ICI. Transcriptomic analysis revealed limited transcriptional effects attributable to immunosurveillance following treatment with either HMB or anti-PD1 alone; however, the combination produced a robust antitumor immune response. Digital cytometry analysis revealed altered immune cell composition in the tumor microenvironment. Conclusion: The combination of HMB with anti-PD1 treatment elicited significant antitumor responses in a murine model of PDAC progression. Given that immunotherapy trials in PDAC have not yet proven effective, even when combined with cytotoxic chemotherapy, our preclinical findings support clinical evaluation of combined ICI and HMB regimens as a therapeutic strategy against PDAC. Citation Format: Suhas K. Etigunta, Michael F. Coleman, Kristyn A. Liu, Alex J. Pfeil, Zhengrong Cui, Stephen D. Hursting. β-Hydroxy-β-methylbutyrate (HMB) sensitizes murine pancreatic ductal adenocarcinoma (PDAC) to immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3507.
Abstract 118: BACH1 is an oxygen-sensitive mediator of the hypoxia response in triple-negative breast cancer
Authors: Christopher M. Dann, Long C. Nguyen, Dongbo Yang, Joseph P. Wynne, Andrea Valdespino, Letícia Stock, Marsha R. Rosner
Journal: Cancer Research (2022)

Abstract Triple-negative breast cancer (TNBC) is an aggressive solid tumor characterized by a hypoxic phenotype that promotes metastatic progression and resistance to therapy. The canonical cellular response to hypoxia is largely driven by hypoxia inducible factors (HIFs) that stimulate transcription of genes related to angiogenesis, cancer stem cells, cell survival, and glucose and iron metabolism. There is growing evidence that several factors, in addition to HIFs, contribute to the tumor hypoxia response. Thus, identifying novel mechanisms that regulate this cellular response in addition to the HIFs is key to our understanding of hypoxia and could have direct clinical impact. High expression of BTB and CNC homology 1 (BACH1), a heme-regulated bZIP transcription factor, drives metastatic progression in various cancers including TNBC. While BACH1 has been shown to be induced under hypoxia in some cell lines, its regulation and role in hypoxia signaling, specifically with regards to cancer cells, is poorly understood. Here we report a novel regulatory pathway of the tumor hypoxia response in TNBC. We show that BACH1 is post-translationally prolyl-hydroxylated by the HIF prolyl-hydroxylases (PHDs) in an oxygen-dependent and NRF2/HMOX1-independent manner. Hypoxic exposure thus stabilizes BACH1 protein and enhances its DNA binding activity at loci of both canonical and hypoxia-specific downstream targets. We further show that BACH1 regulates the hypoxia response by promoting expression of both HIF-dependent and HIF-independent hypoxia-induced genes in TNBC cells. Our findings describe BACH1 as a novel oxygen-sensitive effector of the hypoxia response in TNBC that represents an alternative target for attenuating hypoxia-induced, pro-metastatic signaling and therapeutic resistance. Citation Format: Christopher M. Dann, Long C. Nguyen, Dongbo Yang, Joseph P. Wynne, Andrea Valdespino, Letícia Stock, Marsha R. Rosner. BACH1 is an oxygen-sensitive mediator of the hypoxia response in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 118.
Primary Retroperitoneal Lymph Node Dissection for Patients With Pathologic Stage II Nonseminomatous Germ Cell Tumor—N1, N2, and N3 Disease: Is Adjuvant Chemotherapy Necessary?
Authors: Isamu Tachibana, Sean Q. Kern, Antoin Douglawi, Yan Tong, Mohammad Mahmoud, Timothy A. Masterson, Nabil Adra, Richard S. Foster, Lawrence H. Einhorn, Clint Cary
Journal: Journal of Clinical Oncology (2022)

According to National Comprehensive Cancer Network guidelines, adjuvant chemotherapy (AC) has been advocated after primary retroperitoneal lymph node dissection (RPLND) to reduce the risk of relapse in pathologic nodal (pN) stage pN2 or pN3, whereas surveillance is preferred for pN1. We sought to explore the oncologic efficacy of primary RPLND alone for pathologic stage II in nonseminomatous germ cell tumors (NSGCTs) to reduce overtreatment with chemotherapy.
Screening for Impaired Visual Acuity in Older Adults
Authors: Carol M. Mangione, Michael J. Barry, Wanda K. Nicholson, Michael Cabana, David Chelmow, Tumaini Rucker Coker, Esa M. Davis, Katrina E. Donahue, John W. Epling, Carlos Roberto Jaén, Alex H. Krist, Martha Kubik, Li Li, Gbenga Ogedegbe, Lori Pbert, John M. Ruiz, Melissa A. Simon, James Stevermer, John B. Wong
Journal: JAMA (2022)

<h3>Importance</h3> Impairment of visual acuity is a serious public health problem in older adults. The number of persons 60 years or older with impaired visual acuity (defined as best corrected visual acuity worse than 20/40 but better than 20/200) was estimated at 2.91 million in 2015, and the number who are blind (defined as best corrected visual acuity of 20/200 or worse) was estimated at 760 000. Impaired visual acuity is consistently associated with decreased quality of life in older persons, including reduced ability to perform activities of daily living, work, and drive safely, as well as increased risk of falls and other unintentional injuries. <h3>Objective</h3> To update its 2016 recommendation, the US Preventive Services Task Force (USPSTF) commissioned a systematic review to evaluate the benefits and harms of screening for impaired visual acuity in older adults. <h3>Population</h3> Asymptomatic adults 65 years or older who present in primary care without known impaired visual acuity and are not seeking care for vision problems. <h3>Evidence Assessment</h3> The USPSTF concludes that the evidence is insufficient to assess the balance of benefits and harms of screening for impaired visual acuity in asymptomatic older adults. The evidence is lacking, and the balance of benefits and harms cannot be determined. More research is needed. <h3>Recommendation</h3> The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for impaired visual acuity in older adults. (I statement)
Abstract 1646: Humanized TROP2 mice provide a preclinical tool for the evaluation of therapeutic drugs targeting TROP2
Authors: Dexuan Huang, Zhiyuan Shen, Limei Ma, Chong Li, Tianquan Jin
Journal: Cancer Research (2022)

Abstract Human TROP2, also known as tumor-associated calcium signal transducer 2 (TACSTD2), is a type I cell surface glycoprotein that mediates intracellular calcium signals. It plays a crucial role in cell proliferation, survival, self-renewal, and cell adhesion. Several ligands are found to interact with TROP2, including claudin-1, claudin-7, cyclin D1, and IGF-1. TROP2 is expressed on the surface of many stem and progenitor cells as well as other tissues. Importantly, TROP2 is highly expressed in a variety of solid tumors, making it a new target for the development of antibody-conjugated drugs. To evaluate the efficacy of anti-TROP2 antibodies, we generated a humanized B-hTROP2 mouse at Biocytogen. In this mouse model, the murine TROP2 gene was replaced by the full length human TROP2 gene. Western blot analysis showed that human TROP2 protein expression was detected in skin and kidney of homozygous B-hTROP2 mice. These results suggest that B-hTROP2 mice is an ideal tool for in vivo efficacy evaluation of therapeutic drugs targeting human TROP2. Citation Format: Dexuan Huang, Zhiyuan Shen, Limei Ma, Chong Li, Tianquan Jin. Humanized TROP2 mice provide a preclinical tool for the evaluation of therapeutic drugs targeting TROP2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1646.
Longitudinal Outcome over Two Decades of Unrelated Allogeneic Stem Cell Transplantation for Relapsed/Refractory Acute Myeloid Leukemia: An ALWP/EBMT Analysis
Authors: Arnon Nagler, Maud Ngoya, Jacques-Emmanuel Galimard, Myriam Labopin, Martin Bornhäuser, Matthias Stelljes, Jürgen Finke, Arnold Ganser, Herman Einsele, Nicolaus Kröger, Arne Brecht, Wolfgang Bethge, Matthias Edinger, Aleksandr Kulagin, Jakob Passweg, Igor Wolfgang Blau, Ahmet Elmaagacli, Kerstin Schäfer-Eckart, Uwe Platzbecker, Thomas Schroeder, Donald Bunjes, Johanna Tischer, Sonja Martin, Alexandros Spyridonidis, Sebastian Giebel, Bipin Savani, Mohamad Mohty
Journal: Clinical Cancer Research (2022)

We evaluated outcomes of unrelated transplantation for primary refractory/relapsed (ref/rel) acute myeloid leukemia (AML), comparing two cohorts according to the year of transplant, 2000-2009 and 2010-2019.Multivariable analyses were performed using the Cox proportional-hazards regression model.3,430 patients were included; 876 underwent a transplant between 2000-2009 and 2554 in 2010-2019. Median follow-up was 8.7 (95% CI, 7.8-9.4) and 3.4 (95% CI, 3.1-3.6) years (P < 0.001). Median age was 52 (18-77) and 56 (18-79) years (P > 0.0001); 45.5% and 55.5% had refractory AML while 54.5% and 44.5% had relapsed AML. Conditioning was myeloablative in 60% and 52%, respectively. Neutrophil recovery and day 100 incidence of acute and 2-year incidence of chronic graft-versus-host disease (GvHD) were similar between the two periods. Two-year relapse incidence was higher for patients undergoing transplant in the 2000-2009 period versus those undergoing transplant in 2010-2019: 50.2% versus 45.1% (HR, 0.85; 95% CI, 0.74-0.97; P = 0. 002). Leukemia-free survival; overall survival; and GvHD-free, relapse-free survival were lower for the 2000-2009 period: 26% versus 32.1% (HR, 0.87; 95% CI, 0.78-0.97; P = 0.01), 32.1% versus 38.1% (HR, 0.86; 95% CI, 0.77-0.96; P = 0.01), and 21.5% versus 25.3% (HR, 0.89; 95% CI, 0.81-0.99; P = 0.03), respectively. Two-year nonrelapse mortality was not significantly different (23.8% vs. 23.7%; HR, 0.91; 95% CI, 0.76-1.11; P = 0.34).Outcome of unrelated transplantation for patients with ref/rel AML has improved in the last two decades, rescuing about one third of the patients. See related commentary by Adrianzen-Herrera and Shastri, p. 4167.
Abstract 5005: <i>PSMB9/LMP2</i> as a controversial diagnostic biomarker for uterine leiomyosarcoma
Authors: Raul Maia, Georgia Kokaraki, Jorge E. Souza, Joseph W. Carlson, Tirzah B. Petta
Journal: Cancer Research (2022)

Abstract Uterine leiomyosarcoma (uLMS) are rare and malignant tumors that arise in the cells of the myometrium. Diagnosis is based on histopathological features. Developing effective therapies against uLMS is a challenge due its resistance to conventional radiation and chemotherapy. In vivo and in vitro models for uLMS are urgently needed and it has been proposed that knockout mice for the gene PSMB9 (MIM:177045), also known by LMP2, could be a good model to study uLMS. Previous studies using mice homozygous deficiency for PSMB9 presented abnormalities in the biological functions of the immunoproteasome and spontaneously developed uLMS thus suggesting this gene as a tumor suppressor gene. Furthermore, expression of PSMB9 was suggested to be a specific biomarker for the diagnosis of uLMS. The goal of this study was to evaluate the role of PSMB9 in uLMS using in silico analysis of transcriptomics data from a patient cohort, combined with publicly available datasets. Molecular data were integrated and used for a meta-analysis of RNA-seq in order to find Differentially Expressed Genes (DEGs). A total of 68, 66 and 67 samples from normal myometrium (MM), uterine leiomyoma (LM) and uLMS, respectively, were analyzed. A quality control followed by adapter removal and alignment step was assessed using FastQC, Trim-galore and HISAT2 software respectively and counting reads was performed using htseq-count. Expression values were calculated as Transcripts Per Million (TPM) in order to remove libraries dependencies. Differential expression analysis was done using DESeq2 and edgeR and genes were classified as DEG when that had adjusted p-value &amp;lt; 0.01 and |log2FC| ≥ 2 in both packages. Gene Set Enrichment Analysis was performed using fgsea package with 100,000 permutations and MSigDB collections (KEGG and Reactome) as input parameters. Our results showed an over-expression of PMSB9 in uLMS samples and immune-related pathways were significantly enriched. Moreover, the overall survival analysis for the outcome of uLMS patients based on PSMB9 expression in TCGA showed no significant changes, further questioning the importance of PSMB9 in uLMS malignancy. Finally, based on phylogenetic analysis we showed that PSMB9 conservation between Mus musculus and Homo sapiens is not closely related. This divergence suggests that the biological role of PSMB9 may differ between M. musculus and H. sapiens. Human uLMS exhibits an over-expression in PSMB9 and these findings suggest PSMB9-deficient mice are not an appropriate diagnostic-biomarker for uLMS. Citation Format: Raul Maia, Georgia Kokaraki, Jorge E. Souza, Joseph W. Carlson, Tirzah B. Petta. PSMB9/LMP2 as a controversial diagnostic biomarker for uterine leiomyosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5005.
Abstract 3736: SETD2 aberrancy enhanced the synergetic anti-tumor effects of DNA hypomethylating agents and PARP inhibitors in aggressive clear cell renal cell carcinoma
Authors: Xinyi Zhou, Guanghou Fu, Hong-Tao Li, Hemant Gujar, Daniel J. Weisenberger, David I. Quinn, Bo Han, Gangning Liang
Journal: Cancer Research (2022)

Abstract Purpose: SETD2 aberrancy, as the main reason of depleted levels of H3K36me3, plays an important role in diverse forms of cancer and is most notably in clear cell renal cell carcinoma (ccRCC). Altered chromatin modelers related to impaired H3K36me3 occupancy are linked to renal cancer aggressiveness and metastasis, where the latter dramatically drops the relative 5-year survival rate of ccRCC from 91% to 11%. Developing novel treatment targeting H3K36me3-compromised cancer cell is urgently needed for diagnostic and treatment purposes. Methods: Phenotypic and animal experiments were conducted to test the sensitivity of kidney cancer cells with impaired H3K36me3 to hypomethylating agent (HMA), PARP inhibitor (PARPi), and HMA + PARPi combination treatments. Comet assay, flow cytometry, western blot and bioinformatic analysis were performed to explore the mechanism beneath. Results: Combination treatment of 5-Aza-CdR (DAC) and Talazoparib (PARPi) generate more cytotoxicity in SETD2-altered ccRCC cell lines than in SETD2-intact cell lines, including inhibited cell growth, incomplete colony formation, more apoptosis, increased DNA damage and impaired DNA damage repair. The up-regulation of STING and transposable element (TE), as well as the loss of chromatin stability, were more remarkable in SETD2-altered ccRCC cell lines when treated with DAC + PARPi. Conclusion: Combination treatment of DAC and Talazoparib showed greater synergistic anti-tumor effect in SETD2 aberrant than in SETD2 wild-type ccRCC cells, making it a potential treatment strategy for H3K36me3-compromised cancers. Further pre-clinical studies should be conducted to make a precise medicine-based approach. Citation Format: Xinyi Zhou, Guanghou Fu, Hong-Tao Li, Hemant Gujar, Daniel J. Weisenberger, David I. Quinn, Bo Han, Gangning Liang. SETD2 aberrancy enhanced the synergetic anti-tumor effects of DNA hypomethylating agents and PARP inhibitors in aggressive clear cell renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3736.
Use of Dupilumab and Eosinophil Targeted Therapy in Treating Angiolymphoid Hyperplasia With Eosinophilia
Authors: Kathryn Franke, Eliza Notaro, Ata S. Moshiri, Andrew Ayars, Andrea Kalus
Journal: JAMA Dermatology (2022)

This case report describes a 68-year-old woman who presented with 2 years of fixed diffuse dermal nodules that began to develop on the right neck.
Comparison of lumen-apposing metal stents versus double-pigtail plastic stents for infected necrotising pancreatitis
Authors: Lotte Boxhoorn, Robert C Verdonk, Marc G Besselink, Marja Boermeester, Thomas L Bollen, Stefan AW Bouwense, Vincent C Cappendijk, Wouter L Curvers, Cornelis H Dejong, Sven M van Dijk, Hendrik M van Dullemen, Casper HJ van Eijck, Erwin JM van Geenen, Muhammed Hadithi, Wouter L Hazen, Pieter Honkoop, Jeanin E van Hooft, Maarten AJM Jacobs, June EC Kievits, Marnix PM Kop, Eva Kouw, Sjoerd D Kuiken, Michiel Ledeboer, Vincent B Nieuwenhuijs, Lars E Perk, Jan-Werner Poley, Rutger Quispel, Rogier JJ de Ridder, Hjalmar C van Santvoort, Christina J Sperna Weiland, Martijn WJ Stommel, Hester C Timmerhuis, Ben J Witteman, Devica S Umans, Niels G Venneman, Frank P Vleggaar, Roy LJ van Wanrooij, Marco J Bruno, Paul Fockens, Rogier P Voermans
Journal: Gut (2022)

Objective Lumen-apposing metal stents (LAMS) are believed to clinically improve endoscopic transluminal drainage of infected necrosis when compared with double-pigtail plastic stents. However, comparative data from prospective studies are very limited. Design Patients with infected necrotising pancreatitis, who underwent an endoscopic step-up approach with LAMS within a multicentre prospective cohort study were compared with the data of 51 patients in the randomised TENSION trial who had been assigned to the endoscopic step-up approach with double-pigtail plastic stents. The clinical study protocol was otherwise identical for both groups. Primary end point was the need for endoscopic transluminal necrosectomy. Secondary end points included mortality, major complications, hospital stay and healthcare costs. Results A total of 53 patients were treated with LAMS in 16 hospitals during 27 months. The need for endoscopic transluminal necrosectomy was 64% (n=34) and was not different from the previous trial using plastic stents (53%, n=27)), also after correction for baseline characteristics (OR 1.21 (95% CI 0.45 to 3.23)). Secondary end points did not differ between groups either, which also included bleeding requiring intervention—5 patients (9%) after LAMS placement vs 11 patients (22%) after placement of plastic stents (relative risk 0.44; 95% CI 0.16 to 1.17). Total healthcare costs were also comparable (mean difference −€6348, bias-corrected and accelerated 95% CI −€26 386 to €10 121). Conclusion Our comparison of two patient groups from two multicentre prospective studies with a similar design suggests that LAMS do not reduce the need for endoscopic transluminal necrosectomy when compared with double-pigtail plastic stents in patients with infected necrotising pancreatitis. Also, the rate of bleeding complications was comparable.
Abstract 5259: Clinical feature of end-stage cerebral glioblastomas
Authors: Norihiko Saito, Nozomi Hirai, Naoki Kushida, Sho Sato, Yu Hiramoto, Satoshi Fujita, Haruo Nakayama, Morito Hayashi, Keisuke Ito, Takatoshi Sakurai, Satoshi Iwabuchi
Journal: Cancer Research (2022)

Abstract Glioblastoma is the most common and aggressive primary brain tumor, and even with the best treatment, the tumor repeatedly recurs and grows, eventually invading the entire brain. There are few reports on the pathogenesis and pathological search in the terminal stage of glioblastoma. In this study, we report the pathological analysis of glioblastoma cases that we were able to perform from initial treatment to confirmation of death at our hospital. We analyzed 26 glioblastoma cases (including 18 autopsied cases) treated at our hospital from initial treatment to death. The mean age of the 26 patients was 60.7 years, and the mean overall survival was 16.7 months. The duration of clinical symptoms was 36.2 days from coma to death, and 12 days from the appearance of respiratory depression to death. Psychiatric symptoms and central fever were observed in patients with intrathecal dissemination. Steroids and antiepileptic drugs were often continued after completion of active treatment. Patients with intrathecal dissemination progressed rapidly and presented with a variety of symptoms, including psychiatric symptoms, headache, neck pain, and central fever. In addition, there was a case of diffuse infiltration from the brain parenchyma to the periventricular area in a patient treated with bevacizumab, suggesting the possibility of a change in the form of recurrence. In the terminal stage of glioblastoma, hypoxemia due to disturbance of respiratory center progresses from impaired consciousness to death. Convulsive seizures are rare in the dying stage, and continuation of antiepileptic drugs should be considered. Although many patients develop from local recurrence, it was suggested that new treatment may change the mode of recurrence or alter the trait of tumor cells. In recent years, the number of patients receiving home care and end-of-life care has been increasing due to the improvement of medical systems such as home care. Further investigation of the pathophysiology is necessary for better end-of-life care. Citation Format: Norihiko Saito, Nozomi Hirai, Naoki Kushida, Sho Sato, Yu Hiramoto, Satoshi Fujita, Haruo Nakayama, Morito Hayashi, Keisuke Ito, Takatoshi Sakurai, Satoshi Iwabuchi. Clinical feature of end-stage cerebral glioblastomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5259.